Transmissible spongiform encephalopathies (TSEs) affect a wide range of species including sheep, cattle, mink, humans, deer, elk and others. An issue of particular importance is to determine which TSE diseases can be transmitted to other species especially humans or livestock. To investigate the issue of cross-species transmission of chronic wasting disease (CWD) of deer and elk, we developed two lines of transgenic mice expressing deer prion protein with either the Gly96 or Ser96 naturally occurring deer PrP alleles. So far the Gly 96 mice are susceptible to all four different CWD deer or elk pools tested, whereas the Ser96 mice were not susceptible to any of these pools. This mimics the situation in deer, where animals homozygous for Ser96 are rather resistant to CWD. We have now obtained CWD brain material from an unusual Ser96 CWD-infected deer and will inoculate our Ser96 mice to see whether there might be a unique CWD strain with tropism for this PrP allele. [unreadable] [unreadable] In other studies PrPres levels in brain and lymph node tissues from CWD-infected deer and elk were compared by quantitative western blotting. Whereas all the deer had high PrPres in brain and most lymph nodes, elk had high levels in brain only and much lower levels in lymph nodes. These results support the interpretation that deer might be infected initially by a peripheral route such as oral, resulting in lymphoid infection, followed by neuroinvasion via peripheral nerves. In contrast elk might be infected by ocular, nasal or tongue infection from the environment, followed by direct neuroinvasion via cranial nerves.